The objectives of this project are to study the cartilage and bone inducing factors and to define their role in embryogenesis and in postnatal life, both in tissue formation and in disease. As tissue regeneration recapitulates the developmental sequence of embryonic tissue formation, it is conceivable that understanding the mechanisms of action of the soluble differentiation factors is a key step towards biologically controlled regeneration of skeletal tissues. This will have a significant impact on the treatment of congenital and/or acquired skeletal diseases such as large bone defects, impaired fracture healing, osteoarthritis, osteoporosis and periodontitis. This project focuses on the further characterization of cartilage and bone inducing molecules, members of the TGF-B superfamily, and their biological activities. Using molecular probes, we are studying their respective contributions to cartilage and endochondral and membranous bone formation. Immunohistochemical localization and in situ hybridization of cartilage and bone inducing proteins, as well as studies in vitro and in vivo, indicate the selective contribution of these molecules to initiation, enhancement, maintenance and maturation of the chondrocytic and osteoblastic phenotypes. Molecular genetic approaches reveal the physiological roles of these morphogens in skeletal development.